Characterization and modulation of corticotropin-releasing factor in the neurointermediate pituitary gland.
The present study attempts to determine whether part of the corticotropin-releasing factor (CRF)-like materials present in the 'posterior pituitary' is composed of authentic CRF and examines whether the concentration of that peptide may be modulated by circulating glucocorticoids. Analysis of crude extracts of neurointermediate lobes (NIL) of rat pituitaries by reverse-phase HPLC, coupled with a specific radioimmunoassay (RIA), revealed the presence of a major component eluting with the same retention time as rat CRF (rCRF) and, importantly, which was indistinguishable by RIA from the synthetic peptide. Also, two minor forms eluted earlier than rCRF upon HPLC; one of these forms matched the elution position of r[Met(O)21,38]CRF. All three species did show biological activity and stimulated ACTH release from pituitary cells. Essentially the same elution profile was generated by median eminence (ME) extracts. Immunoreactive CRF (CRFi) content of the NIL was about 3% of that of the ME and was found to undergo a significant increase as a result of long-term adrenalectomy while, in contrast, CRFi content of the ME was decreased. This effect of adrenalectomy was completely antagonized by dexamethasone treatment. This study thus provides strong evidence for the presence of authentic CRF within the NIL of the rat pituitary and also shows that tissue concentration of that peptide was modulated by glucocorticoids.


Complementary patterns of expression of c-ets 1, c-myb and c-myc in the blood-forming system of the chick embryo.
We have used in situ hybridization to study the spatial and temporal distribution of the transcription of three cellular oncogenes encoding DNA-binding proteins, c-ets 1, c-myb and c-myc during the development of the chick embryo. c-ets 1 mRNA expression appears linked to the mesodermal lineage and is strongly expressed in early endothelia; it subsequently becomes restricted to small vessel endothelia. Hemopoietic cells in extraembryonic blood islands at E2 express c-ets 1, while intraembryonic hemopoietic cells in aortic clusters (E3) and paraaortic foci (E6) express c-myb. c-myc transcripts are detected in cells undergoing hemopoiesis in both these extraembryonic and intraembryonic sites. Outside the blood-forming system, c-myc is transcribed in a large variety of cells; c-ets 1 displays tissue-specific expression in groups of mesodermal cells engaged in morphogenetic processes and appears excluded from all epithelia; finally the expression of c-myb is the most tightly linked to hemopoietic cells. In any case, it is clear that these three oncogenes display complementary expression in endothelial and hemopoietic cells where their patterns are modulated in relationship to multiplication and differentiation.


Active metal template synthesis of a neutral indolocarbazole-containing [2]rotaxane host system for selective oxoanion recognition.
An active metal template strategy was used to synthesise a neutral indolocarbazole containing [2]rotaxane anion host system. 1H NMR anion binding investigations reveal that the [2]rotaxane recognises a range of monoanions in acetone-d5 : D2O 95 : 5 with an unusual interlocked host selectivity for acetate and dihydrogenphosphate oxoanions over halides. The rotaxane displays an overall selectivity for the sulfate dianion, favouring a 2 : 1 host : guest binding stoichiometry at low sulfate concentration and a 1 : 1 stoichiometry in the presence of excess sulfate. Fluorescence titration demonstrates that the [2]rotaxane is also capable of sensing guest anions via significant changes in its emission spectrum.


Quality of diagnostic and treatment practices of pulmonary tuberculosis management amongst health practitioners in Haryana, north India.
Early diagnosis and supervised treatment remains the mainstay for tuberculosis (TB) control in India. A facility-based cross-sectional study was conducted to assess diagnostic and treatment practices of tuberculosis management as per the Revised National Tuberculosis Control Programme at a secondary level health facility in north India. This hospital mostly caters to rural and peri-urban populations in the Ballabgarh block of Faridabad district, Haryana. A sample size of 244 was calculated. Consecutive chest symptomatic patients were recruited in the study. Information about socio-demographic characteristics and treatment was obtained from a routine history-taking process in the outpatient clinic. Results were expressed as mean, standard deviation (SD) and odds ratio (OR) with 95% confidence interval (CI). A total of 250 pulmonary TB suspects were recruited, out of which 55.4% were males and mean age of study participants was 35.4 years (SD 14.6). Almost half (47.1%) of the participants had sought treatment from government hospitals, followed by 46.7% from private hospitals. Those who had visited a private facility were significantly more likely not to receive sputum acid-fast bacillus (AFB) diagnostic testing (OR=7.26, 95% CI 4.04-13.08), likely to be taking a second-line anti-TB drug as an antibiotic trial (OR=3.65, 95% CI 1.17-11.30), be empirically taking anti-TB drugs (OR=5.28, 95% CI 1.50-118.64) and getting a serological test done (OR=9.58, 95% CI 1.20-76.0) than those who went to a government health facility. Those who made at least three visits to a private facility were significantly more likely to have taken a second-line anti-TB drug as an antibiotic trial (OR=3.56, 95% CI 1.36- 9.28) and be empirically taking anti-TB drugs (OR=5.75, 95% CI 2.18-15.20) than those that made fewer than three visits. This study documented inappropriate diagnostic and treatment practices in TB management and highlights the need to generate awareness about it among health practitioners in north India.


MicroRNA regulation of liver cancer stem cells.
MicroRNAs (miRNAs), a class of emerging small non-coding RNAs, serve as vital players in modulating multiple biological processes via the post-transcriptional regulation of gene expression. Dysregulated expression of miRNAs in liver cancer is well documented, and the involvement of miRNAs in liver cancer initiation and progression has also been described. Cancer stem cells (CSCs) are a subset of cells known to be at the root of cancer recurrence and resistance to therapy. In this review, we highlight recent reports indicating that miRNAs participate in the regulation of liver cancer stem cells (LCSCs). The Wnt signaling pathway, TGF-beta signaling pathway, JAK/STAT signaling pathway and epithelial-mesenchymal transition (EMT) are all closely correlated with the miRNA modulation of LCSCs. In addition, several miRNAs have been demonstrated to be involved in the regulation of LCSCs in response to therapy sensitivity. Targeting LCSCs by regulating the expression of these miRNAs represents a potential therapeutic strategy for treating cancer drug resistance, metastasis and recurrence in the near future.


[Natural history of human T-lymphotropic virus type 1 (HTLV-1) infection].
The natural history of human T-lymphotropic virus type-1 (HTLV-1) infection has been difficult to be clarified, because only a small proportion of HTLV-1 carriers develop adult T-cell leukemia(ATL) after a long incubation period. We have performed a long-term follow-up study of HTLV-1 carriers for 17 years. Based on the findings of this study and other studies, the natural history of HTLV-1 carriers is hypothesized as follows. The major routes of infection of this virus are from mother to child, between spouses, and through blood products. The target of HTLV-1 infection is CD4 positive peripheral blood mononuclear cells (PBMCs). The number of infected cells is supposed to be increased just after the infection, then decreased in a year. The number of infected cells does not change thereafter during more than 10 years. In 90% of newly infected people, this level is low or medium ranging from less than 0.05% to 5% of PBMCs infected; however, approximately 10% of newly infected people develop into carriers with many number of infected cells as more than 5% of PBMCs infected. Clonal expansion of infected cells is likely to be contributing to the maintenance of the HTLV-1 infection. Replication of certain clones among many infected cells may be accelerated by the expression of Tax protein and some of them develop to have a phenotype to avoid immune surveillance. Finally, some of these clones, which acquired the accumulation of genomic abnormality, develop the pre-leukemic state. The increased number of certain T-cells due to HTLV-1 infection may also cause imbalance of the immune system, resulting in immune dysfunction or inflammatory diseases like myelopathy and uveitis. Therefore, it seems to be important to find ways to prevent HTLV-1 associated diseases among the carriers especially those with many infected cells.


Motor abilities of children and adolescents with a psychiatric condition: A systematic literature review.
To summarize research regarding the motor abilities of children and adolescents who suffer from a common psychiatric condition. In order to outline the current knowledge regarding the motor abilities of children and adolescents with autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), disruptive behavior disorders (DBD) and depression, a comprehensive systematic literature search was carried out using PubMed, Medline and ERIC databases. The databases were searched for relevant English language articles published between January 1990 and April 2014. Only studies that conducted a quantitative evaluation of motor ability and concerned individuals aged 0-18 years were included. A separate search was conducted for each disorder (ASD, ADHD, DBD, depression) in conjunction with each of the following keywords: (psycho/perceptuo) motor/movement skill(s), (psycho/perceptuo) motor/movement abilities, (psycho/perceptuo) motor/movement impairment, (psycho/perceptuo) motor/movement problem(s), motor function, motor coordination, motor performance, motor deficit(s). To detect supplementary relevant literature, the reference lists of the retrieved articles were examined. The search strategy yielded 51 studies meeting the inclusion criteria. In total, 28 studies were included that examined the motor abilities of children and adolescents with ASD. All studies indicated that they performed below average on various standardized motor assessment instruments. The overall prevalence rate for impairment in motor abilities ranged from 33% to 100%. Twenty-seven studies examined the motor abilities of children and adolescents with ADHD. Depending on the type of motor assessment tool and the cut-off points used by different researchers, prevalence rates of impairment in motor abilities are highly variable and ranged from 8% to 73%. Remarkably, there is a paucity of research addressing the motor abilities of individuals with DBD or depression. Furthermore, methodological problems, such as measurement and comorbidity issues, complicate the generalization of the findings. Research suggests that motor impairment is highly prevalent in some psychiatric conditions, particularly ASD and ADHD. However, future work is necessary to draw sound conclusions.


A Novel Physical Sensing Principle for Liquid Characterization Using Paper-Based Hygro-Mechanical Systems (PB-HMS).
In recent years paper-based microfluidic systems have emerged as versatile tools for developing sensors in different areas. In this work; we report a novel physical sensing principle for the characterization of liquids using a paper-based hygro-mechanical system (PB-HMS). The PB-HMS is formed by the interaction of liquid droplets and paper-based mini-structures such as cantilever beams. The proposed principle takes advantage of the hygroscopic properties of paper to produce hygro-mechanical motion. The dynamic response of the PB-HMS reveals information about the tested liquid that can be applied to characterize certain properties of liquids. A suggested method to characterize liquids by means of the proposed principle is introduced. The experimental results show the feasibility of such a method. It is expected that the proposed principle may be applied to sense properties of liquids in different applications where both disposability and portability are of extreme importance.


Cloning and expression of Tsaiya duck liver fatty acid binding protein.
Liver basic fatty acid (FA)-binding protein (Lb-FABP) cDNA was cloned from the livers of laying Tsaiya ducks and used to generate probes for quantification of the Lb-FABP mRNA in Tsaiya ducks. The full-length Lb-FABP cDNA of the Tsaiya duck was highly homologous with that of the mallard (99%), chicken (88%), and iguana (73%). The amino acid sequence was also highly homologous to Lb-FABP found in birds and reptiles, indicating a similar function of the Tsaiya duck Lb-FABP to those species. The calculated molecular weight for the cloned duck Lb-FABP was 14,043g/mol. The Lb-FABP was highly expressed in the liver of laying Tsaiya ducks and not detectable in heart, ovary, intestine, or adipose tissues. The expression of Tsaiya duck Lb-FABP in the skeletal muscle was also detected, and the sequence was confirmed. The greater expression of the hepatic Lb-FABP in the egg-laying Tsaiya ducks than the prelaying ducks paralleled the higher FA use by the laying ducks. These results suggest that hepatic Lb-FABP may be needed for egg production when FA metabolism is high for the ducks. Feeding laying Tsaiya ducks with diets enriched with 2% docosahexaenoic acid (DHA) oil for 2 wk significantly increased hepatic DHA content compared with in ducks fed a 2% butter basal diet. There was no effect of dietary DHA enrichment on the expression of Lb-FABP in the liver of Tsaiya ducks. The results suggest that even though the Lb-FABP may be involved in hepatic FA metabolism, the effect of individual FA on liver Lb-FABP in laying Tsaiya ducks needs to be further studied.


Regions With Low Rates of Bystander Cardiopulmonary Resuscitation (CPR) Have Lower Rates of CPR Training in Victoria, Australia.
Bystander cardiopulmonary resuscitation (CPR) more than doubles the chance of surviving an out-of-hospital cardiac arrest. Recent data have shown considerable regional variation in bystander CPR rates across the Australian state of Victoria. This study aims to determine whether there is associated regional variation in rates of CPR training and willingness to perform CPR in these communities. We categorized each Victorian postcode as either a low or high bystander CPR region using data on adult, bystander-witnessed, out-of-hospital cardiac arrests of presumed cardiac etiology (n=7175) from the Victorian Ambulance Cardiac Arrest Registry. We then surveyed adult Victorians (n=404) and compared CPR training data of the respondents from low and high bystander CPR regions. Of the 404 adults surveyed, 223 (55%) resided in regions with low bystander CPR. Compared with respondents from high bystander CPR regions, respondents residing in regions with low bystander CPR had lower rates of CPR training (62% versus 75%, P=0.009) and lower self-ratings for their overall knowledge of CPR (76% versus 84%, P=0.04). There were no differences between the regions in their reasons for not having undergone CPR training or in their willingness to perform CPR. Rates of survival for bystander-witnessed, out-of-hospital cardiac arrests were significantly lower in low bystander CPR regions (15.7% versus 17.0%, P<0.001). This study found lower rates of CPR training and lower survival in regions with lower rates of bystander CPR in Victoria, Australia. Targeting these regions with CPR training programs may improve bystander CPR rates and out-of-hospital cardiac arrest outcomes.


Nrf2 antioxidant pathway suppresses Numb-mediated epithelial-mesenchymal transition during pulmonary fibrosis.
Epithelial mesenchymal transition (EMT) is a key progression that promotes pulmonary fibrosis (PF). Numb, a phosphotyrosine-binding domain (PTB) protein, is implicated with EMT. Nuclear factor erythroid 2-related factor2 (Nrf2) and its downstream proteins heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) constitute an important pathway of antioxidant defense signal for protecting against PF. It remains elusive whether Nrf2 antioxidant pathway and Numb have a potential relationship in EMT-mediated PF. Here, we observed the effects of Nrf2 pathway and Numb on bleomycin(BLM)-induced PF in Nrf2-knockout (Nrf2-/-) and wild-type (WT) mice. Meanwhile, rat type II alveolar epithelial cells line (RLE-6TN) and human epithelial cells line (A549) were both treated with an Nrf2 activator sulforaphane (SFN), or transfected siRNAs of Nrf2 and Numb to unravel roles of Nrf2 pathway, Numb and the link between them on transforming growth factor β1 (TGF-β1)-induced EMT. We found BLM-induced lung fibrosis were more severe in Nrf2-/- mice compared to WT mice with reduced expressions of HO-1 and NQO1. Numb was enhanced with down-regulated expressions of Nrf2 in BLM groups and further increased in Nrf2-/- groups. In vitro, given exogenous TGF-β1 on RLE-6TN and A549 up-regulated Numb expressions, accompanied with down-regulations of Nrf2 and its target proteins HO-1 and NQO1. Transfected with Nrf2 and Numb siRNAs further aggravated and relieved the progression of EMT, respectively. Inversely, activating Nrf2 pathway by SFN reduced the expression of Numb and EMT-related protein. Moreover, Numb deficiency by siRNA relieved the protection of activating Nrf2 against EMT. In conclusion, activating Nrf2 antioxidant pathway suppresses EMT during PF via inhibiting the abnormal expression of Numb. These findings provide insight into PF pathogenesis and a basis for novel treatment approaches.


Material selection for GRIN-based achromatic doublets.
We use first-order optical principles to examine the ability of gradient index (GRIN) lenses to correct chromatic aberrations. We consider radial GRIN lenses with flat surfaces, with a flat diffractive surface, and with curved surfaces. We model the GRIN material system as a locally varying, subwavelength blend of three materials. In this model, we demonstrate that the color-correcting properties of each lens type can be expressed solely in terms of the dispersion properties of the base materials. We find, at this level of approximation, that the material condition for a two-material GRIN achromat with curved surfaces is identical to that for a homogeneous doublet achromat comprised of the same two materials. For the more general case of three-material, ternary GRIN elements, we use the theory to develop a figure-of-merit-based optimization approach. This allows us to identify promising material combinations without first fabricating a GRIN element. The optimization approach can be applied to alternate GRIN geometries and arbitrary glass catalogs. We use our model to search a large, commercial glass catalog to identify the best achromatic glass combinations for the three different GRIN lenses described above. Significant numerical effort was required to identify which glass combinations performed best. Ternary glass combinations are necessary to achieve good achromatic performance for flat geometries. Diffraction combined with a graded-index enables improved color correction for the same optical power or nearly a factor of two increase in power for the same level of color correction. Glass pairs that perform well as an achromatic doublet also perform well chromatically when blended in a GRIN singlet.


[Clinical picture of differentiated thyroid carcinoma in the T1 stage].
Patients with thyroid microcarcinoma have usually excellent prognosis. However, recurrences in neck and distant metastases have been reported. The optimal treatment for this group of patients is still discussed. The aim of study was to present the clinical and histopathological data of our group of patients with differentiated thyroid carcinoma of 1 cm or less in size diagnosed from 1990 to 2000. 146 patients (137 females and 9 males, mean age 47 years) with differentiated thyroid carcinoma up to 1 cm in the greatest dimension were analyzed. The median follow-up time was 3.5 years. The diagnosis was incidental (made after primary surgery) in 82% of cases. In 85% of patients papillary thyroid carcinoma was diagnosed (in 6% of them as follicular variant). Histopathological risk factors were noticed in 32 patients (21%). The patients were operated in different surgical clinics in Poland. 5% (8) of primary operations and 51% (33) of secondary ones were performed in our center. The most frequent primary operation was bilateral, subtotal strumectomy (62%). Total thyroidectomy was made in 14% of cases (21). Secondary radical operation was performed in 65 patients (44%). Residual cancer was found in 9% of reoperated patients. 47% of patients (69) were treated with 131I and all of them were administered hormonal therapy to suppress TSH. No recurrence and distant metastases were observed. Lymph node metastases were diagnosed and treated in 10 patients (7%). During observation period 1 patient died because of breast cancer. No statistically significant influence of clinical and histopathological risk factors or operation type on clinical outcome was observed. In the analyzed group secondary surgery was connected with the higher risk of complications. In thyroid papillary microcarcinoma total thyroidectomy is recommended for patients with multiple foci of neoplasm or with metastases (lymph node or distant). Establishment of optimal treatment in minimal follicular thyroid cancer is not possible on the basis of our data and published literature.


An evaluation of sealing ability of endodontic materials as root canal sealers.
An in vitro dye leakage study was carried out to compare the apical microleakage of vitapex (calcium hydroxide based paste) when used with single gutta percha cone with that of dentalis KEZ (calcium hydroxide and zincoxide eugenol based sealer) and zincoxide-eugenol sealer when used with laterally condensed gutta percha obturation technique. One hundred single rooted human anterior teeth were instrumented and randomly divided into three experimental groups of 30 teeth each and two control groups of 5 teeth each. Teeth in the first group were obturated using a single master gutta percha cone and vitapex as root canal sealer and those of second group were obturated with laterally condensed gutta percha using dentalis KEZ as sealer. Third experimental group was filled with laterally condensed gutta-percha using zinc-oxide eugenol as sealer. Teeth were then suspended in 2% methylene blue. After this, teeth were demineralized dehydrated and cleared. Linear dye penetration was determined under stereomicroscope (x10) with calibrated eye piece. Results of this study showed that calcium hydroxide based endodontic material leaked comparatively less as compared to zinc oxide Eugenol sealer. Vitapex with single gutta-percha cone provided an adequate apical Seal against dye penetration.


Near-IR Absorbing J-Aggregate of an Amphiphilic BF2 -Azadipyrromethene Dye by Kinetic Cooperative Self-Assembly.
A new amphiphilic BF2 -azadipyrromethene (aza-BODIPY) dye 1 has been synthesized using a CuI -catalyzed "click" reaction. For this dye, two self-assembly pathways that lead to different type of J-aggregates with distinct near-infrared optical properties have been discovered. The metastable off-pathway product displays a broad, structureless absorption band while the thermodynamically stable on-pathway aggregate exhibits the characteristic spectral features of a J-aggregate, that is, red-shifted intense absorption band with significantly narrowed linewidth. The morphology and structure of the aggregates were studied by atomic force microscopy, transmission and scanning electron microscopy. The aggregation processes of 1 were investigated by temperature- and concentration-dependent UV/Vis spectroscopy and evaluated by models for cooperative self-assembly.


Anomalous Left Coronary Artery from Pulmonary Artery: An Important Cause of Ischemic Mitral Regurgitation in Children.
Anomalous left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital anomaly. The usual presentation in infancy is inconsolable crying or congestive cardiac failure, both due to myocardial ischemia. Survivors after infancy have improved left ventricular function but continue to have mitral regurgitation due to papillary muscle ischemia. The present study emphasizes the importance of unexplained mitral regurgitation as a clue to the diagnosis. Patients with the diagnosis of ALCAPA operated between June 2017 and May 2018 were enrolled. Their ages at diagnosis, electrocardiography, and echocardiography findings were noted. A selective angiogram of the right coronary artery was done in all. Results of surgical reimplantation were analyzed. Postoperative data were collected, including ventricular function and mitral regurgitation. Six patients were included. Clinical signs of cardiac failure were present in two patients, and a systolic murmur was heard in all. The mean left ventricular ejection fraction was 52 ± 12%. Mitral regurgitation was present in all of the patients. The right coronary artery was dilated (Z score > 2.5) in all except one. Selective right coronary angiogram and cardiac computerized tomography angiogram (CTA) were performed in all. Coronary reimplantation was successfully done. Follow-up echocardiography showed improved left ventricular ejection fraction and degree of mitral regurgitation in all patients. ALCAPA is an uncommon congenital anomaly, the diagnosis of which can be missed, particularly in late presenters. Unexplained mitral regurgitation should always raise the suspicion of this anomaly. Surgical intervention has excellent results with an improvement of left ventricular function and mitral regurgitation.


Conservation of histone carcinogen adducts during replication: implications for long-term molecular dosimetry.
The effect of cell replication on histone-carcinogen adducts was investigated by determining the specific adduct levels as a function of time following carcinogen treatment of human TK6 cells grown in culture. Core histones isolated from cells treated with aflatoxin B1 or r-7,t-8 dihydroxy-t-9,t-10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene exhibited a decrease over five generations in specific adduct level that did not exceed the decrease expected as a result of dilution with newly synthesized protein except during the early phase (< 1 generation) of the experiment when loss of chemically unstable adducts might occur. Similar kinetics without the initial, more rapid phase was observed when cells were treated with N-nitroso-N-methylurea. Multigeneration stability of aflatoxin B1 and N-nitroso-N-methylurea adducts that formed on histone H1 was also observed; in these experiments it was not possible to determine if there was an initial phase in the kinetics. These experiments indicate that cell replication does not result in the repair or removal of adducted histones, establishing the feasibility of using histone-carcinogen adducts for molecular dosimetry purposes.


The effectiveness of oral appliances in elderly patients with obstructive sleep apnoea treated with lorazepam--a pilot study.
Obstructive sleep apnoea (OSA) is one of the most common sleep disorders in elderly and represents a special problem for elderly patients. Elderly patients use a large number of drugs that might have an influence on the upper airway structure, anxiolytics or benzodiazepines being the most common. The aim of this study was to examine the effectiveness of mild or moderate OSA treatment with mandibular advance oral appliance in older lorazepam users compared with the age-matched lorazepam-free patients. A total of 40 functionally independent patients with the age of 65-74 were enrolled in the study. All included patients were found to suffer from at least two of the existing OSA symptoms (snoring, sleep fragmentation, daytime sleepiness) and were diagnosed with mild or moderate OSA after nocturnal polysomnography. Patients were divided into two groups. The experimental group consisted of 20 patients who used lorazepam in their daily therapy, and a control group consisted of 20 patients who did not take lorazepam. A mandibular advance appliance was made individually for each patient. Patients involved in the study were not overweight and were suggested to practise sleeping on the side and reduce alcohol consumption during the study. The study has shown that mandibular advance oral appliances were responsible for complete control of the OSA in over 37% of cases (15 patients). Patients have also reported substantial improvement in the symptoms; 80% of them reported that they had snored less, slept better (94%) and have not experienced daytime sleepiness (100%).


Oxycodone lengthens reproductions of suprasecond time intervals in human research volunteers.
Oxycodone, a popularly used opioid for treating pain, is widely abused. Other drugs of abuse have been shown to affect time perception, which, in turn, may affect sensitivity to future consequences. This may contribute to continued use. This study evaluated the effect of oxycodone on time perception in normal healthy volunteers. For this within-subject, double-blind design study, participants performed a temporal reproduction task before and after receiving placebo or oxycodone (15 mg, orally) over six outpatient sessions. Participants were first trained with feedback to reproduce three standard intervals (1.1, 2.2, and 3.3 s) in separate blocks by matching response latency from a start signal to the duration of that block's standard interval. During testing, participants were instructed to reproduce the three intervals from memory without feedback before and after drug administration. Oxycodone significantly lengthened time estimations for the two longer intervals relative to placebo. These results suggest that opioids alter temporal processing for intervals greater than 1 s, raising questions about the effect of these drugs on the valuation of future consequences.


Buprenorphine reverses neurocognitive impairment in EcoHIV infected mice: A potential therapy for HIV-NCI.
Thirty-eight million people worldwide are living with HIV, PWH, a major public health problem. Antiretroviral therapy (ART) revolutionized HIV treatment and significantly increased the lifespan of PWH. However, approximately 15-50% of PWH develop HIV associated neurocognitive disorders (HIV-NCI), a spectrum of cognitive deficits, that negatively impact quality of life. Many PWH also have opioid use disorder (OUD), and studies in animal models of HIV infection as well as in PWH suggest that OUD can contribute to HIV-NCI. The synthetic opioid agonist, buprenorphine, treats OUD but its effects on HIV-NCI are unclear. We reported that human mature inflammatory monocytes express the opioid receptors MOR and KOR, and that buprenorphine reduces important steps in monocyte transmigration. Monocytes also serve as HIV reservoirs despite effective ART, enter the brain, and contribute to HIV brain disease. Using EcoHIV infected mice, an established model of HIV infection and HIV-NCI, we previously showed that pretreatment of mice prior to EcoHIV infection reduces mouse monocyte entry into the brain and prevents NCI. Here we show that buprenorphine treatment of EcoHIV infected mice with already established chronic NCI completely reverses the disease. Disease reversal was associated with a significant reduction in brain inflammatory monocytes and reversal of dendritic injury in the cortex and hippocampus. These results suggest that HIV-NCI persistence may require a continuing influx of inflammatory monocytes into the brain. Thus, we recommend buprenorphine as a potential therapy for mitigation of HIV brain disease in PWH with or without OUD.


Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment.
Immune cells in the tumour microenvironment not only fail to mount an effective anti-tumour immune response, but also interact intimately with the transformed cells to promote oncogenesis actively. Signal transducer and activator of transcription 3 (STAT3), which is a point of convergence for numerous oncogenic signalling pathways, is constitutively activated both in tumour cells and in immune cells in the tumour microenvironment. Constitutively activated STAT3 inhibits the expression of mediators necessary for immune activation against tumour cells. Furthermore, STAT3 activity promotes the production of immunosuppressive factors that activate STAT3 in diverse immune-cell subsets, altering gene-expression programmes and, thereby, restraining anti-tumour immune responses. As such, STAT3 propagates several levels of crosstalk between tumour cells and their immunological microenvironment, leading to tumour-induced immunosuppression. Consequently, STAT3 has emerged as a promising target for cancer immunotherapy.


Trimeric assembly of the C-terminal region of thrombospondin-1 or thrombospondin-2 is necessary for cell spreading and fascin spike organisation.
Thrombospondin-1 (TSP-1) and the highly related protein thrombospondin-2 (TSP-2) are trimeric extracellular molecules that have complex roles in wound healing, angiogenesis and matrix organisation. At the cellular level, TSP-1 supports cell adhesion and migration by the organisation of fascin spike cytoskeletal structures. To define the molecular requirements for assembly of fascin spikes by thrombospondins, we developed a panel of recombinant protein units of TSP-1 and TSP-2; these were designed according to the domain boundaries and included matched monomeric and trimeric units. These proteins were tested for their effects on cell attachment and fascin spike organisation using C2C12 skeletal myoblasts and vascular smooth muscle cells. In monomeric units, cell attachment activity was localised to the type 1 repeats or type 3 repeats/C-terminal globule, and both regions need to be present in the same molecule for maximal activity. On a molar basis, cell-attachment activities with monomeric units were low compared with intact TSP-1, and no monomeric unit induced cell spreading. Trimeric versions of the type 1 repeats were more adhesive but did not induce cell spreading. Strikingly, trimers that contained the type 3 repeats/C-terminal globule of either TSP-1 or TSP-2 supported cell spreading and fascin spike organisation, producing a similar activity to intact TSP-1. We conclude that trimeric assembly of the highly conserved TSP C-terminal region is necessary for organisation of the fascin-based cytoskeletal structures that are needed for thrombospondin-induced cell motility.


ETA and ETB receptors differentially modulate afferent and efferent arteriolar responses to endothelin.
The segment-specific actions of endothelin peptides and agonists have not been thoroughly investigated in the renal microcirculation. The current studies were performed to assess the relative contribution of ET(A) and ET(B) receptors to the renal pre- and postglomerular arteriolar responses to ET-1. Experiments determined the effect of selective ET(A) (A-127722; 30 nM) and ET(B) (A-192621; 30 nM) receptor blockade, on arteriolar responses to ET-1 concentrations of 1 pM to 10 nM in rat kidneys using the isolated juxtamedullary nephron technique. Renal perfusion pressure was set at 110 mmHg. Baseline afferent arteriolar diameter was similar in all groups and averaged 17.8+/-0.6 microm (n=14). In control experiments (n=6), ET-1 produced significant concentration-dependent decreases in arteriolar diameter, with 10 nM ET-1 decreasing diameter by 85+/-1%. Selective blockade of ET(A) receptors (n=6) prevented ET-1-mediated vasoconstriction, except at concentrations of 1 and 10 nM. Similarly, the vasoconstrictor profile was right shifted during selective ET(B) receptor blockade (n=4). Combined ET(A) and ET(B) receptor blockade (n=5) completely abolished afferent arteriolar diameter responses to ET-1. ET(B) selective agonists (S6c and IRL-1620) produced disparate responses. S6c produced a concentration-dependent vasoconstriction of afferent arterioles. In contrast, S6c produced a concentration-dependent dilation of efferent arterioles that could be blocked with an ET(B) receptor antagonist. IRL-1620, another ET(B) agonist, was less effective at altering afferent or efferent diameter and produced a small reduction in pre- and postglomerular arteriolar diameter. These data demonstrate that both ET(A) and ET(B) receptors participate in ET-1-mediated vasoconstriction of afferent arterioles. ET(B) receptor stimulation provides a significant vasodilatory influence on the efferent arteriole. Furthermore, since selective ET(A) and ET(B) receptor antagonists abolished preglomerular vasoconstrictor responses at lower ET-1 concentrations, these data support a possible interaction between ET(A) and ET(B) receptors in the control of afferent arteriolar diameter.


Zona pellucida glycoproteins based immunocontraceptive vaccines: strategies for development and their applications.
The mammalian oocyte is surrounded by an extra-cellular matrix, the zona pellucida (ZP), composed of three major glycoproteins (ZP1, ZP2 and ZP3). The ZP glycoproteins, by virtue of their tissue specificity and critical role during mammalian fertilization, have emerged as potential candidate antigens for the development of an immunocontraceptive vaccine. Molecular characterization of ZP glycoproteins from several species, reveals a variable degree of homology among the deduced primary amino acid sequences, which provided an opportunity to undertake active immunization studies in heterologous animal models. Active immunization of various animal species with either native ZP glycoproteins or those obtained by recombinant DNA technology led to the inhibition of fertility. Thus ZP glycoproteins based immunocontraceptive vaccines offer an attractive proposition for controlling wild life population. To make it a practical proposition, additional research inputs are required to optimize and devise novel strategies for vaccine delivery. Observed ovarian dysfunction, often associated with immunization by ZP glycoproteins is one of the major stumbling blocks for their use in humans. Ongoing studies to delineate appropriate B cell epitopes of ZP glycoproteins that are devoid of oophoritogenic T-cell epitopes, which will inhibit fertility without concomitant oophoritis, will be critical to determine their feasibility for human use.


Feeding and Swallowing Issues in Autism Spectrum Disorders.
Children with autism spectrum disorder (ASD) often experience difficulties related to communication and behaviour. However, their feeding issues are most distressing to their families and healthcare professionals as they impact on the children's adaptive function and health. In comparison to typically developing children, those with ASD experience significantly more feeding difficulties. Children with ASD may display distinctive feeding difficulties and atypical feeding behaviours that include picky eating, limited independent feeding, need for increased feeding times, and a highly restrictive food repertoire. Many of these feeding difficulties continue into childhood, persist in adolescence, and even spill over into adulthood. This proves to be a formidable challenge, as feeding is an essential component for healthy nutrition, growth, and development. This article will highlight how particular food items that are eaten and preferred by affected children may be contributing to their exhibited feeding difficulties. Next, it will be shown how the children's restrictive diets supplant more healthy food options. When this is combined with the children's noted reduced physical activity, the consequences are especially serious, as they include not only malnutrition but also give rise to childhood obesity. In sum, it will be demonstrated that feeding difficulties in young children with ASD are not well understood nor managed. The dearth of knowledge about feeding issues in this population affects both assessment choices and, specifically, management practices - aspects that will be elaborated on in this article. Conclusions will include suggested future directions for enhancing and complementing knowledge of these issues for stakeholders.


Elucidation of Anionic and Cationic Redox Reactions in a Prototype Sodium-Layered Oxide Cathode.
The ever-increasing demand for large-scale energy storage has driven the prosperous investigation of sodium-ion batteries (NIBs). As a promising cathode candidate for NIBs, P2-type Na2/3Ni1/3Mn2/3O2 (NaNMO), a prototype sodium-layered oxide, has attracted extensive attention because of its high operating voltage and high capacity density. Although its electrochemical properties have been extensively investigated, the fundamental charge compensation mechanism, that is, the cationic and anionic redox reactions, is still elusive. In this report, we have systematically investigated the transition metal and oxygen redox reactions of NaNMO nanoflakes using bulk-sensitive soft X-ray absorption spectroscopy and full-range mapping of resonant inelastic X-ray scattering from an atomic-level view. We show that the bulk Mn3+/Mn4+ redox couple emerges from the first discharge process with the increment of inactive Mn3+ upon cycling, which may have a negative effect on the cyclability. In contrast, the bulk Ni redox mainly stems from the Ni2+/Ni3+ redox couple, in contrast to the conventional wisdom of the Ni2+/Ni4+ redox couple. The quantitative analysis provides unambiguous evidence for the continuous reduction of the average valence state of Mn and Ni over extended cycles, leading to the voltage fading. In addition, we reveal that the oxygen anions also participate in the charge compensation process mainly through irreversible oxygen release rather than reversible lattice oxygen redox. Such understanding is vital for the precise design and optimization of NaNMO electrodes for rechargeable NIBs with outstanding performance.


Primary pleuropulmonary synovial sarcoma mimicking a carcinoid tumor: Case report and literature review.
Primary pleuropulmonary synovial sarcoma is a rare malignancy. Commonly described radiologic features in the literature include pleural disease and/or effusion, lack of calcification and high uptake on positron emission tomography computerised tomography. A 68-year-old woman presented with a 3-month history of cough. Imaging studies showed a right upper lobe mass with internal foci of calcification, endobronchial extension, and low fluorodeoxyglucose avidity on positron emission tomography computerised tomography, leading to an initial diagnosis of carcinoid tumor. However, histologic specimens suggested an unexpected diagnosis of aggressive synovial sarcoma, and the case was referred to the sarcoma MDT. Metastatic synovial sarcoma was ruled out, and radical surgical excision of the lesion was performed. This article highlights the multiple atypical features of primary pleuropulmonary synovial sarcoma as seen in this case and reviews imaging findings described in the literature. Radiologists should be aware of this unusual yet aggressive type of sarcoma.


Requirement of gamma-carboxyglutamic acid residues for the biological activity of Gas6: contribution of endogenous Gas6 to the proliferation of vascular smooth muscle cells.
Gas6 (encoded by growth-arrest-specific gene 6) is a gamma-carboxyglutamic acid (Gla)-containing protein which is released from growth-arrested vascular smooth muscle cells (VSMCs) and potentiates VSMC proliferation induced by Ca2+-mobilizing growth factors, but not that induced by receptor tyrosine kinases. In this study we examined the importance of Gla residues for the biological activities of Gas6 and tried to assess the importance of endogenous Gas6 in VSMC proliferation. We demonstrated that Gla-deficient Gas6 lacked receptor-binding and growth-potentiating activities. Therefore the vitamin K-dependent modification of Gas6 appeared to be essential for its biological activities. Next we used warfarin, an inhibitor of vitamin K-dependent gamma-carboxylation, to estimate the contribution of endogenous Gas6 to VSMC proliferation. Warfarin markedly inhibited the thrombin-induced proliferation of VSMC without affecting the mRNA or protein expression of Gas6. Therefore the inhibition seems to be due to prevention of the vitamin K-dependent modification of Gas6. However, warfarin did not affect epidermal growth factor-induced proliferation. A neutralizing antibody against Gas6 gave a similar result, i.e. it inhibited thrombin-induced VSMC proliferation but not that induced by epidermal growth factor. These results indicate that endogenously produced Gas6 is very important for VSMC proliferation induced by Ca2+-mobilizing growth factors.


Estimating multimodal brain connectivity in multiple sclerosis: an exploratory factor analysis.
Graph-theoretical approaches have become a popular way to model brain data collected using magnetic resonance imaging (MRI), both from the structural and the functional perspectives. In structural networks, tract-based mapping allows to model different aspects of brain structures by means of the specific characteristics of the different MRI modalities. However, there has been little effort to join the information carried by each modality and to understand what level of common variance is shown in these data. In this paper, we proposed a combined approach based on graph theory and factor analysis to model magnetization transfer and microstructural properties in 18 relapsing remitting multiple sclerosis (RRMS) patients and 17 healthy controls. After defining the common factors and outlining their relationships with MRI data, we evaluated between-group differences using global and local graph measures. The results showed that one common factor describes brain structures in terms of myelin and global integrity, and such factor is able to highlight specific between-group differences.


[Systemic mechanisms of advanced reflection of probability events in disease].
Using the systems approach, the paper considers the nodal mechanisms and the value of advanced reflection of the reality (a warning response) at different levels of vital activity in health and disease. It is suggested that a warning response retains in disease, though the advanced reflection may be transformed depending on the severity of the body's disorders and the efficiency of performance of functional systems. In disease, there are three types of the systems: 1) usual functional systems with the same properties of warning responses as those in health which prevent lesions and their progression, 2) systems whose performance result is both useful and adverse, 3) functional systems whose performance result leads to impaired vital activity or contributes to their generalization (abnormal systems). The mechanisms of dual and damaging effects of the systems are disclosed. The author concludes that in disease even in a dying process, there are only changes in the level and, occasionally, nature of a warning response, but it preserves until a person is alive.


Is there an underclass in Britain?
This paper sets out to define the underclass and then test the predictions of three competing theories in the underclass debate. Using the National Child Development Study for the analysis it is found that an 'underclass' suffering from a lack of qualifications, low cognitive ability and chronic joblessness exists. The validity of making a distinction between the working class and an 'underclass' has often been questioned both because of the dubious history of such a distinction and because it is not believed that such a distinction is empirically true. The results in this paper contradict this assertion by finding the underclass to be distinctive from the working class in terms of patterns of family formation, work commitment and political allegiance. The distinct attitudes of the underclass, when coupled with evidence of inter- and intra-generational stability of membership, provide early evidence that a new social class, the underclass, may now exist in Britain.


Interaction with phospholipids modulates alpha-synuclein nitration and lipid-protein adduct formation.
Intracellular aggregates of alpha-syn (alpha-synuclein) represent pathoanatomical hallmarks of neurodegenerative disorders (synucleinopathies). The molecular mechanisms underlying alpha-syn aggregation into filamentous inclusions may involve oxidation and nitration of the protein. Whereas the effects of oxidants and nitrating species on soluble alpha-syn have been studied in detail, the effect of these reactive species on alpha-syn associated with lipids is still unknown. In the present paper, we report that alpha-syn bound to small unilamellar liposomes composed of phosphatidylcholine/phosphatidic acid is resistant to oxidation and nitration when compared with soluble alpha-syn. Additionally, increasing concentrations of unsaturated fatty acids diminished the oxidation and nitration of alpha-syn upon exposure to fluxes of peroxynitrite (8-20 microM x min(-1)). To investigate the effect of oxidized lipids on alpha-syn, the protein was incubated with the bifunctional electrophile 4-HNE [4-hydroxy-2(E)-nonenal]. MS analysis showed the formation of three major products corresponding to the native protein and alpha-syn plus one or two 4-HNE molecules. Trypsin digestion of the modified protein followed by peptide 'finger-printing' revealed that 4-HNE modified the peptide E46GVVHGVATVAEK58. Further analysis of the peptides with liquid chromatography-tandem MS identified the modified residue as His50. The data indicate that the association of alpha-syn with biological membranes protects the protein from oxidation and nitration and thus diminishes the formation of protein molecules capable of forming aggregates. However, products of lipid peroxidation can also modify alpha-syn, generating novel protein adducts that could serve as biomarkers for documenting oxidative processes in human as well as animal and cellular models of alpha-syn aggregation and pathology.


Whole-body distribution of radioactivity after intraperitoneal administration of 32P colloids.
The whole-body distribution of radioactivity after intraperitoneal instillation of 32P-labelled chromic hydroxide particles has been studied in patients operated for early-stage ovarian cancer. Gamma-camera imaging of the abdominal 32P-distribution revealed that the administration procedure was critical for obtaining a homogeneous plating of the radiocolloids on the serosal surface. Dose calculations based on a uniform distribution of 32P in a capillary layer covering the intraperitoneal surface gave an estimated tissue surface dose of about 30 Gy per 370 MBq of 32P administered. The amount of 32P in peripheral blood increased for seven days after instillation followed by a continuous decrease. Bone marrow concentration was from two to five times as high as that in blood, but the total amounts were too small to give significant radiation doses. Gel chromatography showed that 33% of the activity in blood consisted of high molecular weight material, probably colloids. The remainder of the activity (67%) was attached to material of very low molecular weight, appearing as a consequence of physiological degradation of the colloids.


The Deep Fascia of the Infraorbital Region, Deep Plane, and Suprafibromuscular Facelift: New Anatomy for Safer Facelifting.
Deep-plane rhytidectomy, first described by Skoog, has had a resurgence in popularity and is in high demand today. We describe anatomical findings that establish the presence of a true deep fascia in the midface, we named as Chiara's fascia, like the first author's first name, which helps to form the facial ligaments and is contiguous with the superficial layer of the deep temporal fascia. This fascia inserts on the periosteum of the inferior orbital rim at the arcus marginalis and separates the suborbicularis oculi fat (SOOF) from the preperiosteal fat. This distinct fascial layer lies under the superficial fascia or superficial musculoaponeurotic system (SMAS) and represents the floor of what is commonly termed the "deep plane." When this fascial highway is identified intraoperatively, blunt dissection immediately superficial to this layer will protect facial nerve branches overlying the muscles lifting the upper lip such as the zygomaticus. Subsequent dissection over the middle and lower face can usually be performed bluntly. Over a 10-year period, a total of 100 hemifaces were dissected with a 100% success rate of identifying this fascia in all specimens. This work was further validated by examining histologic specimens that clearly demonstrate this unique fibrofatty fascial layer. These dissections and new anatomical findings were then correlated to over 300 intraoperative deep-plane facelift cases by the primary and senior authors. We term this operative technique as the suprafibromuscular facelift. Dissection in this plane allows for safe release of facial retaining ligaments with protection of facial nerve branches.


Early diagnosis of radiodermatitis using lactate dehydrogenase isozymes in hairless mice (SKH1-hr).
In this study, we evaluate a method for the early diagnosis of radiodermatitis for use in the prevention and therapy of this condition. Hairless mice (SKH1-hr) were used to study the early diagnosis of radiodermatitis. Lactate dehydrogenase (LDH, EC 18.104.22.168) isozymes were analyzed using native-polyacrylamide gel electrophoresis and western blotting of blood serum and tissues collected from SKH1-hr mice. Radiodermatitis developed 24 days after the first X-irradiation. Reduced spleen weight was observed after the last X-irradiation (P<0.05). Thereafter the weight increased until 24 days after the first irradiation, finally reaching levels comparable to those in the sham-irradiated control group. LDH activity was the highest in skeletal muscle and lowest in blood serum. LDH C(4), A(4), A(3)B, A(2)B(2), AB(3), and B(4) isozymes were detected, in the mentioned order, from the cathode. This result was similar in other mouse strains. In the irradiated group, LDH A(4) isozyme levels were reduced in the serum until inflammation occurred, whereas those of B(4) isozyme were elevated. The subunits A and B followed a similar trend to that of LDH A(4) and B(4) isozyme, respectively. Importantly, antibodies against LDH B(4) isozyme could prove useful in the early diagnosis of radiodermatitis.


Determination of spectroscopic constants from rovibrational configuration interaction calculations.
Rotational constants and centrifugal distortion constants of a molecule are the essence of its rotational or rovibrational spectrum (e.g., from microwave, millimeter wave, and infrared experiments). These parameters condense the spectroscopic characteristics of a molecule and, thus, are a valuable resource in terms of presenting and communicating spectroscopic observations. While spectroscopic parameters are obtained from experimental spectra by fitting an effective rovibrational Hamiltonian to transition frequencies, the ab initio calculation of these parameters is usually done within vibrational perturbation theory. In the present work, we investigate an approach related to the experimental fitting procedure, but relying solely on ab initio data obtained from variational calculations, i.e., we perform a nonlinear least squares fit of Watson's A- and S-reduced rotation-vibration Hamiltonian to rovibrational state energies (resp. transition frequencies) from rotational-vibrational configuration interaction calculations. We include up to sextic centrifugal distortion constants. By relying on an educated guess of spectroscopic parameters from vibrational configuration interaction and vibrational perturbation theory, the fitting procedure is very efficient. We observe excellent agreement with experimentally derived parameters.


Applicability of SSVEP-based brain-computer interfaces for robot navigation in real environments.
Brain-computer interfaces have been extensively studied and used in order to aid patients suffering from neuromuscular diseases to communicate and control the surrounding environment. Steady-state visual evoked potentials (SSVEP) constitute a very popular BCI stimulation protocol, due to their efficiency and quick response time. In this study, we developed a SSVEP-based BCI along with a low-cost custom radio-controlled robot-car providing live video feedback from a wireless camera mounted on the robot, serving as our testbed. Our goal was to quantitatively assess the applicability of SSVEPs in real time navigation in realistic environments using a pragmatic approach. In order to assess the additional fatigue that the camera video introduces, we designed a two-session experiment, a control one with no connection to the robot and, thus, no live camera feed, and a realistic one where the users could navigate the robot with the provision of front scenes, captured from the camera. Statistical tests revealed a significant decrease of the accuracy of the system during the realistic session that included live video, in comparison with the session that did not. The results suggest that the moving camera image sequence introduces an extra level of fatigue and/or distraction to the users.


Sexually-transmitted viral diseases in women: clinical and epidemiological aspects and advances in laboratory diagnosis.
Sexually transmitted diseases (STDs) have long been known, but they have only recently been recognized as causes of significant long-term morbidity, mainly as a result of increased knowledge concerning viral STDs. The relationship of these diseases with conditions such as anogenital cancer and acquired immunodeficiency syndrome (AIDS) has made viral STDs an important issue in the healthcare of women and infants, and in reproductive health. The evolution of the AIDS pandemic is now characterized by growing differences between rich and poor nations. New diagnostic tools include rapid tests of blood, urine and saliva samples. New techniques, such as computerized cytology, have been developed for the diagnosis of human papillomavirus (HPV). Women infected with HIV are at a greater risk of being co-infected with HPV, and they are also more prone to the progression and persistence of HPV lesions. The herpes simplex virus presents high rates of co-infection with HIV, and it plays a particularly important role in increasing transmission rates of this virus.


[Magnetic resonance in dural post-puncture headache in patient with cerebrospinal fluid hypotension].
Magnetic resonance imaging (MRI) has allowed us to establish a set of radiologic signs associated with intracranial hypotension syndrome. Findings are partly influenced by cerebral displacement. Intracranial hypotension syndrome is characterized by a decrease in cerebrospinal fluid (CSF) pressure to less than 60 mm H2O associated with occipital headache radiating to the frontal and temporal zones. For diagnostic purposes, the most common cause is anesthetic or therapeutic dural puncture, although spontaneous CSF leakage can occur. CSF protein and lymphocyte counts may be high, while the cranial meninges biopsy is normal. MRI images may show a descended brain, taking the start of the sylvian aqueduct and the location of the cerebellar amygdalae as points of reference; diminished size of the subarachnoidal cisterns and occasionally of the cerebral ventricles; meningeal enhancement from increased uptake of the contrast solution; subdural hygromas and hematomas; and pituitary enlargement. Paraspinal fluid and dilated epidural veins may be observed. Radiologic images and clinical signs are related. When CSF pressure is very low, there is greater meningeal enhancement, subdural collection and cerebral displacement. Findings gradually disappear as symptoms diminish. The signs and symptoms that might develop during intracranial hypotension syndrome vary according to the brain structure that might be affected during descent, repositioning and the traction of anchoring structures. MRI allows the degree of cerebral and spinal involvement to be ascertained, to predict whether resolution of the clinical picture will be early or late and to visualize the effect of approaches to reducing CSF leakage.


Intercourse doesn't hasten onset of labor.
Sexual intercourse at term pregnancy is not associated with earlier delivery. In this cohort, the mean gestational age at delivery was actually a few days older. We can throw out the common belief that intercourse hastens the onset of labor and delivery.


Understanding Host-Pathogen Interactions with Expression Profiling of NILs Carrying Rice-Blast Resistance Pi9 Gene.
Magnaporthe oryzae infection causes rice blast, a destructive disease that is responsible for considerable decrease in rice yield. Development of resistant varieties via introgressing resistance genes with marker-assisted breeding can eliminate pesticide use and minimize crop losses. Here, resistant near-isogenic line (NIL) of Pusa Basmati-1(PB1) carrying broad spectrum rice blast resistance gene Pi9 was used to investigate Pi9-mediated resistance response. Infected and uninfected resistant NIL and susceptible control line were subjected to RNA-Seq. With the exception of one gene (Pi9), transcriptional signatures between the two lines were alike, reflecting basal similarities in their profiles. Resistant and susceptible lines possessed 1043 (727 up-regulated and 316 down-regulated) and 568 (341 up-regulated and 227 down-regulated) unique and significant differentially expressed loci (SDEL), respectively. Pathway analysis revealed higher transcriptional activation of kinases, WRKY, MYB, and ERF transcription factors, JA-ET hormones, chitinases, glycosyl hydrolases, lipid biosynthesis, pathogenesis and secondary metabolism related genes in resistant NIL than susceptible line. Singular enrichment analysis demonstrated that blast resistant NIL is significantly enriched with genes for primary and secondary metabolism, response to biotic stimulus and transcriptional regulation. The co-expression network showed proteins of genes in response to biotic stimulus interacted in a manner unique to resistant NIL upon M. oryzae infection. These data suggest that Pi9 modulates genome-wide transcriptional regulation in resistant NIL but not in susceptible PB1. We successfully used transcriptome profiling to understand the molecular basis of Pi9-mediated resistance mechanisms, identified potential candidate genes involved in early pathogen response and revealed the sophisticated transcriptional reprogramming during rice-M. oryzae interactions.


Aggressive management of pulmonary embolism.
Pulmonary embolism (PE) and deep vein thrombosis are two elements of the same pathophysiological process referred to as venous thromboembolism. PE occurs when a thrombus migrates from a deep vein to the pulmonary arteries. Although the true incidence of PE is not known, it is estimated that 530,000 cases of PE occur annually in the United States. Clinical presentation varies from asymptomatic (incidentally diagnosed) to fatal. Development of symptoms depends on the embolic burden and the severity of any underlying cardiopulmonary disease. Several treatment options are available for patients diagnosed with PE. The mainstay of treatment is anticoagulation, but given the high mortality associated with some presentations of symptomatic PE, some advocate more aggressive therapy. In this article we discuss such therapies and their potential and appropriate use.


Role of the hypophysis in regulation of pancreatic and gastric somatostatin.
Since hypophysectomy and GH deficiency are associated with decreases in hypothalamic content and release of SRIF, it was of interest to determine whether these hormonal alterations also affect peripheral tissue levels of SRIF. Hypophysectomized (hypox) rats were studied at various times after surgery and compared with age-matched controls. Pancreatic, gastric, and hypothalamic SRIF levels were measured by RIA and expressed as nanograms per mg protein or nanograms per organ. Decreased levels of hypothalamic SRIF were observed in hypox animals at all time periods after surgery. In contrast, pancreatic SRIF concentrations increased within 1 week of hypophysectomy, and the tissue content increased as much as 3-fold after 20 weeks. Measurement of the SRIF content of isolated rat islets of Langerhans revealed a 67% increased content/islet in hypox rats compared with controls. The gastric SRIF concentration was not changed early, but subsequently, the total organ content was significantly decreased compared with that in controls. The changes in stomach and pancreas SRIF contents became more marked with duration of pituitary deficiency. Studies in genetically dwarfed Snell mice, lacking primarily GH but also other anterior pituitary hormones, were similar to the findings noted in hypox rats; the SRIF concentration was significantly increased in the pancreas and decreased in the stomach and hypothalamus. It is probable that deficiencies in other hormones as well as GH are involved in producing the changes in pancreatic SRIF in hypox and dwarfed animals. This contention was supported in that replacement of T3 (5 micrograms/kg . day) reduced pancreatic SRIF concentration by 30%, while GH plus T3 produced a significantly greater (60%) decrease in pancreatic SRIF in hypox rats.


Effect of long-term exposure to air pollution on anxiety and depression in adults: A cross-sectional study.
The association between exposure to air pollutants and mental disorders among adults has been suggested, although results are not consistent. To analyze the association between long-term exposure to air pollution and history of anxiety and depression disorders and of medication use (benzodiazepines and antidepressants) in adults living in Barcelona. A total of 958 adults (45-74 years old) residents in Barcelona, most of them having at least one of their parents diagnosed with dementia (86%), and participating in the ALFA (Alzheimer and Families) study, were included. We used Land Use Regression (LUR) models to estimate long-term residential exposure (period 2009-2014) to PM2.5, PM2.5 absorbance (PM2.5 abs), PM10, PM coarse, NO2 and NOx. Between 2013 and 2014 participants self-reported their history of anxiety and depression disorders and related medication use. The analysis was focused on those participants reporting outcome occurrence from 2009 onwards (until 2014). We observed an increased odds of history of depression disorders with increasing concentrations of all air pollutants [e.g. an increased odds of depression of 2.00 (95% CI; 1.37, 2.93) for each 10μg/m3 NO2 increase]. Such associations were consistent with an increased odds of medication use in relation to higher concentrations of air pollutants [e.g. an increased odds of antidepressants use of 1.23 (1.04, 1.44) for each 20μg/m3 NOx increase]. Associations regarding anxiety disorders did not reach statistical significance. Our study shows that increasing long-term exposure to air pollution may increase the odds of depression and the use of antidepressants and benzodiazepines. Further studies are needed to replicate our results and confirm this association.


Neurological and functional status 1 year after acute spinal cord injury: estimates of functional recovery in National Acute Spinal Cord Injury Study II from results modeled in National Acute Spinal Cord Injury Study III.
In the second National Acute Spinal Cord Injury Study (NASCIS II) investigators evaluated several standard neurological parameters but not functional activity. This has led to questions concerning the clinical importance of the increase in neurological recovery observed following administration of methylprednisolone (MP) within 8 hours of acute spinal cord injury (SCI). The safety of the therapy has also been questioned. Both neurological and functional recovery were assessed in NASCIS III, a trial that followed an almost identical protocol to NASCIS II. In the current analysis locally weighted scatterplot smoothing (LOESS) nonparametric regression is used to model the extent of recovery in the Functional Independence Measure (FIM) that is predicted by improvement in the NASCIS/American Spinal Cord Injury Association motor scores that were documented in NASCIS III 1 year after SCI, and the models are applied to the extent of motor recovery demonstrated in NASCIS II. The models predict improvement in FIM that would be expected from the motor function recovery observed in NASCIS II. Estimates are provided overall and for patients with complete and incomplete neurological loss at time of injury. The authors review recent evidence obtained from randomized studies documenting adverse effects that may result from high-dose MP therapy. The relationship between motor function and FIM is strongly nonlinear and dependent on initial level of injury and degree of injury severity. In the best statistical model, the expanded motor score could be used to explain 77.2% of the variability in the FIM. Based on the mean MP-related 3.6-unit improvement in the motor score for patients with complete injuries and 7.3 for those with incomplete injuries owed to MP in NASCIS II, 18.6% of patients would improve six or more FIM points and 9% nine or more points, respectively. In those with complete neurological injury, the mean motor improvement of 3.6 predicted that 63.9% of the patients would improve three or more FIM points and 12.1% six or more points to a maximum of eight points. Of those with incomplete neurological injury, a 7.3 mean improvement in motor function predicted that 27.4% would gain six or more FIM points and that 21% would gain nine or more points to a maximum of 15 points. Analysis of the current best evidence from SCI and other randomized surgical trials in which high-dose MP has been administered provides no grounds for concern about commonly studied adverse effects. The extent of MP therapy-related motor function recovery observed in NASCIS II predicted clinically important recovery in the FIM. Reasons to be cautious with regard to this prediction include the lack of robustness in statistical modeling, some loss of validity in the FIM, and considerable heterogeneity in the SCI population. Whatever functional activity is ascribed to high-dose MP therapy, it is does not appear to be associated with risk of adverse outcomes.


Novel fetal imaging techniques.
Fetal imaging technology is evolving rapidly, and new techniques are being evaluated to establish their role in the assessment of the fetus. It is essential that these methods of fetal imaging are carefully assessed to ascertain if they provide additional information to assist in the clarification or understanding of fetal disease states that is not already provided by current conventional imaging techniques.


Six-minute walk test: reference values and prediction equation in healthy boys aged 5 to 12 years.
This study aimed to (1) generate normative data in healthy boys aged 5-12 years for the six-minute walk test (6MWT), an outcome measure currently used in clinical trials in Duchenne muscular dystrophy (DMD), (2) to describe the relation with anthropometric variables and myometry, and (3) to compare our data with published equations. The 6MWT was conducted in 442 boys according to a standardized protocol, as currently used in clinical trials in DMD. Maximal voluntary isometric contractions for knee flexion and extension were recorded with a hand-held myometer. The 6MWD increased significantly with age, from 478.0 ± 44.1 m at age 5, to 650.0 ± 76.8 m at age 12, with the steepest increase between 5 and 8 years. Age- and height related percentile curves of the 6MWD were developed. Correlations with anthropometric variables were fair to good (age r = 0.60, height r = 0.57, weight r = 0.44). Myometric variables (knee flexors and extensors) showed correlations of 0.46 and 0.50 respectively. When dividing into two age categories (5-8 years, 9-12 years), these magnitudes of correlations only applied to the younger age group. Additionally, predicted values were calculated according to available reference equations (Geiger and Ben Saad), indicating an overestimation by those equations. Finally, the Geiger equation was refitted to our population. The percentile curves according to age and height provide a useful tool in the assessment of ambulatory capacity in boys aged 5 to 12 years. Significant correlations with anthropometric variables and myometry were only found in the 5-8 years age group. The Geiger prediction equation, currently used to assess ambulatory capacity in DMD was refitted to obtain a more accurate prediction model based on a large sample with a homogenous distribution across the age categories 5 to 12 years and applying the methodology as currently used in clinical trials in DMD.


Exploring tryptamine conjugates as pronucleotides of phosphate-modified 7-methylguanine nucleotides targeting cap-dependent translation.
Eukaryotic translation initiation factor 4E (eIF4E) is overexpressed in many cancers deregulating translational control of the cell cycle. mRNA 5' cap analogs targeting eIF4E are small molecules with the potential to counteract elevated levels of eIF4E in cancer cells. However, the practical utility of typical cap analogs is limited because of their reduced cell membrane permeability. Transforming the active analogs into their pronucleotide derivatives is a promising approach to overcome this obstacle. 7-Benzylguanosine monophosphate (bn7GMP) is a cap analog that has been successfully transformed into a cell-penetrating pronucleotide by conjugation of the phosphate moiety with tryptamine. In this work, we explored whether a similar strategy is applicable to other cap analogs, particularly phosphate-modified 7-methylguanine nucleotides. We report the synthesis of six new tryptamine conjugates containing N7-methylguanosine mono- and diphosphate and their analogs modified with thiophosphate moiety. These new potential pronucleotides and the expected products of their activation were characterized by biophysical and biochemical methods to determine their affinity towards eIF4E, their ability to inhibit translation in vitro, their susceptibility to enzymatic degradation and their turnover in cell extract. The results suggest that compounds containing the thiophosphate moiety may act as pronucleotides that release low but sustainable concentrations of 7-methylguanosine 5'-phosphorothioate (m7GMPS), which is a translation inhibitor with in vitro potency higher than bn7GMP.


Antimicrobial resistance and antimicrobial use animal monitoring policies in Europe: Where are we ?
The World Health Organization has recognized antimicrobial resistance as one of the top three threats to human health. Any use of antibiotics in animals will ultimately affect humans and vice versa. Appropriate monitoring of antimicrobial use and resistance has been repeatedly emphasized along with the need for global policies. Under the auspices of the European Union research project, EFFORT, we mapped antimicrobial use and resistance monitoring programs in ten European countries. We then compared international and European guidelines and policies. In resistance monitoring, we did not find important differences between countries. Current resistance monitoring systems are focused on food animal species (using fecal samples). They ignore companion animals. The scenario is different for monitoring antibiotics use. Recently, countries have tried to harmonize methodologies, but reporting of antimicrobial use remains voluntary. We therefore identified a need for stronger policies.


Pott's disease? AIDS-associated Mycobacterium heckeshornense spinal osteomyelitis and diskitis.
Acid-fast bacillus (AFB) spinal osteomyelitis in a patient with AIDS is often presumed to be caused by reactivated Mycobacterium tuberculosis. However, other AFB pathogens can mimic M. tuberculosis and, to ensure appropriate and adequate therapy, should be considered by clinicians. We present a case of aggressive spinal osteomyelitis caused by Mycobacterium heckeshornense in an AIDS patient; a review of the literature is also included.


Acceleration of hypertensive cerebral injury by the inhibition of xanthine-xanthine oxidase system in stroke-prone spontaneously hypertensive rats.
It is well-known that, in ischemic cerebral injury, a free radical and its byproducts are generated by xanthine-xanthine oxidase system and eliminated by scavengers such as superoxide dismutase (SOD), catalase, uric acid and ascorbic acid. To investigate the possible involvement of the xanthine-xanthine oxidase system in hypertensive cerebral injury, we examined chronological changes in uric acid level in the cerebral cortex and the effects of the inhibition of xanthine oxidase or catalase using stroke-prone spontaneously hypertensive rats (SHRSP). In young SHRSP, uric acid content was lower than age-matched Wistar-Kyoto rats (WKY), but in mature SHRSP strongly exposed to oxidative stress uric acid content had risen dramatically. Administration of allopurinol, an inhibitor of xanthine oxidase, caused a marked decrease in uric acid content. In these SHRSP, cerebral injury was much more intense compared to the control group. On the other hand, administration of aminotriazole, an inhibitor of catalase, did not affect the brain pathology of SHRSP, in spite of a mild reduction in tissue uric acid content. These results suggest that the xanthine-xanthine oxidase system is not the major source of free radical generation in hypertensive cerebral injury. Moreover, the results also suggest that tissue uric acid may have a key role for the incidence of hypertensive cerebral injury in SHRSP.


A consensus sequence for binding of SmcR, a Vibrio vulnificus LuxR homologue, and genome-wide identification of the SmcR regulon.
Quorum sensing has been implicated as an important global regulatory system controlling the expression of numerous virulence factors in bacterial pathogens. In the present study, DNA targets of SmcR, a Vibrio vulnificus LuxR homologue, were selected from a random pool of DNA fragments by using a cycle selection procedure consisting of in vitro DNA-SmcR interaction, purification of SmcR-DNA complexes, and PCR amplification of SmcR-bound DNA. The amplified DNA fragments were cloned and analyzed separately by electrophoretic mobility shift assay to verify the specific binding of SmcR to the DNA. The DNA sequences bound by SmcR were determined by DNase I footprinting, and alignment of the resulting 29 sequences revealed a 22-bp consensus SmcR-binding sequence, 5'-TTATTGATWWRWTWNTNAATAA-3' (where W represents A or T, R is G or A, and N is any nucleotide), with an 8-bp (TTATTGAT) inverted repeat. The consensus sequence revealed greater efficiency for the binding of SmcR than the SmcR-binding sequence previously identified within P(vvpE). Mutational analysis demonstrated that the 9th and 10th bases from the center are the most essential for SmcR binding. A genome-wide search using the consensus sequence predicted that at least 121 genes are under the control of SmcR, and 10 of these newly identified SmcR regulon members were verified as being regulated by SmcR in V. vulnificus as well as in vitro. The consensus sequence and newly identified genes should be of use for elucidating the regulatory mechanism of SmcR and provide further insight into the role of the quorum sensing in V. vulnificus pathogenesis.


Controlled-release oxycodone is better tolerated than intravenous tramadol/metamizol for postoperative analgesia after retinal-surgery.
We assessed the clinical efficacy and tolerance of controlled-release oxycodone (CRO), comparing it with intravenous tramadol/metamizol combination in this prospective, randomised, double-blind study of 35 ASA physical status I-III patients undergoing retinal-surgery. General anaesthesia using remifentanil and propofol was performed for surgery. On arrival in the recovery room patients were randomly allocated to two groups. The controlled-release oxycodone group (CRO Group) received 10 mg CRO. 12 h after the initial dose another 10 mg CRO were administered. Simultaneously with the initial CRO dose, and every 4 h up to 24 h postoperatively, the CRO Group received intravenous isotonic saline infusion. On arrival in the recovery room the tramadol/metamizol group (TM Group) received a placebo tablet, and 12 h later a second placebo. Simultaneously 100 mg tramadol combined with 1 g metamizol were administered intravenously every 4 h until 24 h postoperatively. All patients had access to intravenous opioid rescue medication. The AUC for quality of analgesia was significantly higher in the CRO Group than in the TM Group (p = 0.0023). Patient rated quality of analgesia significantly higher in the CRO Group than in the TM Group 8 h (p = 0.048), 16 h (p = 0.009) and 24 h (p = 0.001) postoperatively. There was no statistical difference in AUC for pain scores between groups (p = 0.205). The CRO Group experienced significantly less nausea than the TM Group (p = 0.012). Six patients in the TM Group in contrast to none in the CRO Group interrupted the study before finishing the study protocol (p = 0.022). We conclude that CRO administered twice in the first 24 h postoperatively is superior to intravenous tramadol/metamizol for postoperative analgesia after retinal surgery, with fewer adverse events and greater patient satisfaction.


Sulfoxide as a ligand in iron(II) porphyrinates: S- or O-bound?
In order to study the bonding of sulfoxides to iron(II) porphyrinates, an equilibrium study of Fe(TPP) with tetramethylenesulfoxide (TMSO) has been performed. UV-vis spectra at different concentrations of TMSO have shown distinct character belonging to three species: four-coordinate Fe(II)(TPP), five-coordinate [Fe(II)(TPP)(TMSO)], and six-coordinate [Fe(II)(TPP)(TMSO)2]. The isosbestic points for the low TMSO concentrations suggest that the equilibrium constant K1 is much larger than K2. Analysis of spectral data by the nonlinear least-squares program SQUAD gives K1 = 267 and K2 approximately 1. Even though the five-coordinate species is the dominant species under the synthetic conditions, only the six-coordinate species was crystallized and characterized by an X-ray diffraction study. [Fe(TPP)(TMSO)2] (C52H44Fe-N4O2S2): monoclinic, P2(1)/c, a = 11.2580(3) A, b = 15.9262(5) A, c = 12.3930(4) A, beta = 116.246(1) degrees , V = 1992.95(10) A3, Z = 2. X-ray crystallography demonstrates the complex is a low-spin bis-TMSO ligated species. The average Fe-Np distance is 1.999(4) A. The most important feature is that TMSO is coordinated to iron(II) by the sulfur donors, not oxygen. The Fe-S distance is 2.2220(3) A.


Nucleobase-Modified PNA Suppresses Translation by Forming a Triple Helix with a Hairpin Structure in mRNA In Vitro and in Cells.
Compounds that bind specifically to double-stranded regions of RNA have potential as regulators of structure-based RNA function; however, sequence-selective recognition of double-stranded RNA is challenging. The modification of peptide nucleic acid (PNA) with unnatural nucleobases enables the formation of PNA-RNA triplexes. Herein, we demonstrate that a 9-mer PNA forms a sequence-specific PNA-RNA triplex with a dissociation constant of less than 1 nm at physiological pH. The triplex formed within the 5' untranslated region of an mRNA reduces the protein expression levels both in vitro and in cells. A single triplet mismatch destabilizes the complex, and in this case, no translation suppression is observed. The triplex-forming PNAs are unique and potent compounds that hold promise as inhibitors of cellular functions that are controlled by double-stranded RNAs, such as RNA interference, RNA editing, and RNA localization mediated by protein-RNA interactions.


Expression of matrix metalloproteinases 2 and 9 in odontogenic myxoma in vivo and in vitro.
Odontogenic myxoma is a benign neoplasm, which presents local invasiveness and tendency for recurrence. Matrix metalloproteinases (MMPs) 2 and 9 are involved in tumor invasion. Thus, the aim of this study was to analyze the expression and activity of these MMPs in odontogenic myxoma in vivo and in vitro. Three cases of odontogenic myxoma and cultured cells derived from this tumor (Mix1 cell line) were used. The detection and activity of two MMPs (2 and 9) were performed by immunohistochemistry in formalin-fixed, paraffin-embedded sections of odontogenic myxoma and immunofluorescence of the cultured cells and, by gelatin zymographic analysis of Mix1 conditioned media, respectively. MMPs 2 and 9 were detected in vivo and in vitro. The zymographic assay detected latent MMP-2 as well as latent and active MMP-9. Based on our findings, we suggest that MMPs may be involved in local invasiveness of the odontogenic myxoma. MMP-9 is not only secreted by odontogenic myxoma but also has enzyme activity with no further stimulation. Other MMPs were not analyzed; however, our results suggest that the invasive behaviour of odontogenic myxoma could be related at least to MMP-9.


Beta-adrenoceptors in the transplanted human heart: unaltered beta-adrenoceptor density, but increased proportion of beta 2-adrenoceptors with increasing posttransplant time.
To study whether in the (denervated) transplanted human heart beta-adrenoceptors are up-regulated we determined in right ventricular endomyocardial biopsies (weighing 2-7 mg) of 8 heart transplant recipients beta-adrenoceptor density and beta 1:beta 2-adrenoceptor ratio in weekly, later monthly intervals for 6-18 posttransplant months. beta-adrenoceptor density was assessed by 1-2 concentration (-)-[125I]-iodocyanopindolol (ICYP, 200 and 150 pmol/l) binding, the beta 1:beta 2-adrenoceptor ratio by a beta 1-adrenoceptor saturating concentration of the selective beta 1-adrenoceptor antagonist CGP 20712 A (500 nmol/l). In biopsies taken from the donor hearts immediately before transplantation beta-adrenoceptor density was 64.5 +/- 6.3 fmol ICYP bound/mg protein (n = 5), the beta 1:beta 2-adrenoceptor ratio 81.2 +/- 2.2:18.8 +/- 2.2%. beta-Adrenoceptor density did not change during the whole period investigated; it was in the first 9 posttransplant weeks 73.1 +/- 8.3 (n = 22) and after 4-18 months 74.2 +/- 7.6 fmol/mg protein (n = 16). In contrast, with increasing posttransplant time beta 1:beta 2-adrenoceptor ratio was shifted towards beta 2-adrenoceptors: in the first 9 weeks it was 80:20% (n = 17), after 16 weeks 75:25% (n = 10) and after 25-80 weeks 65:35% (n = 7). We conclude that in the first 18 posttransplant months beta-adrenoceptors in the transplanted human heart are not up-regulated. There is, however, a gradual decline in beta 1- and increase in beta 2-adrenoceptors with increasing posttransplant time. As noradrenaline acts in the human heart solely at beta 1-adrenoceptors, while adrenaline activates both beta 1- and beta 2-adrenoceptors with about the same potency, with increasing posttransplant time (and increasing proportion of beta 2-adrenoceptors) adrenaline may play an important role for regulation of contractility and/or heart rate in heart transplant recipients.


A dog with squamous cell carcinoma in the middle ear.
An 8-year-old, castrated male golden retriever was referred for lethargy and inappetance. Severe pain was elicited on palpation of the left temporomandibular joint region. Computed tomography revealed aggressive bone destruction of the left bulla. Squamous cell carcinoma was diagnosed. Malignant tumor in the canine middle ear is rare.


Induction of Extra Claws on the Chelipeds of a Crayfish, Procambarus clarkii.
In a crayfish, Procambarus clarkii, growth of an extra claw was induced by making a V-shaped wound in the proximal end of the propodus of the second and third chelipeds. Two nerve bundles were damaged by the wounding. Some type of extra growth developed on the propodi of 13 of the damaged chelipeds: a pair of extra claws (2 chelipeds), a pair of extra dactyls (1 cheliped), a single extra dactyl (2 chelipeds), and a single slight projection (8 chelipeds). The extra claws and dactyls developed from the peripheral side of the propodus away from the wound site. One of a pair of extra dactyls and the single extra dactyls could be moved only slightly, either manually or by the crayfish. The other extra dactyls could be moved by the crayfish. Muscles were associated with each of the extra and primary claws. The muscles attached to the double extra claw or dactyl were innervated by nerve bundles that were branches from the primary thick nerve bundles. One possible explanation for these findings is that the severed nerve fibers in the thick nerve bundles regenerate, elongate into aberrant roots, and form extra claws or dactyls.


Increased paternal corticosterone exposure influences offspring behaviour and expression of urinary pheromones.
Studies have shown that paternal stress prior to conception can influence the innate behaviours of their offspring. The evolutionary impacts of such intergenerational effects are therefore of considerable interest. Our group previously showed in a model of daily stress that glucocorticoid treatment of adult male mouse breeders prior to conception leads to increased anxiety-related behaviours in male offspring. Here, we aimed to understand the transgenerational effects of paternal stress exposure on the social behaviour of progeny and its potential influence on reproductive success. We assessed social parameters including social reward, male attractiveness and social dominance, in the offspring (F1) and grand-offspring (F2). We report that paternal corticosterone treatment was associated with increased display of subordination towards other male mice. Those mice were unexpectedly more attractive to female mice while expressing reduced levels of the key rodent pheromone Darcin, contrary to its conventional role in driving female attraction. We investigated the epigenetic regulation of major urinary protein (Mup) expression by performing the first Oxford Nanopore direct methylation of sperm DNA in a mouse model of stress, but found no differences in Mup genes that could be attributed to corticosterone-treatment. Furthermore, no overt differences of the prefrontal cortex transcriptome were found in F1 offspring, implying that peripheral mechanisms are likely contributing to the phenotypic differences. Interestingly, no phenotypic differences were observed in the F2 grand-offspring. Overall, our findings highlight the potential of moderate paternal stress to affect intergenerational (mal)adaptive responses, informing future studies of adaptiveness in rodents, humans and other species.


Measurement of attacks and interferences with health care in conflict: validation of an incident reporting tool for attacks on and interferences with health care in eastern Burma.
Attacks on health care in armed conflict and other civil disturbances, including those on health workers, health facilities, patients and health transports, represent a critical yet often overlooked violation of human rights and international humanitarian law. Reporting has been limited yet local health workers working on the frontline in conflict are often the victims of chronic abuse and interferences with their care-giving. This paper reports on the validation and revision of an instrument designed to capture incidents via a qualitative and quantitative evaluation method. Based on previous research and interviews with experts, investigators developed a 33-question instrument to report on attacks on healthcare. These items would provide information about who, what, where, when, and the impact of each incident of attack on or interference with health. The questions are grouped into 4 domains: health facilities, health workers, patients, and health transports. 38 health workers who work in eastern Burma participated in detailed discussion groups in August 2013 to review the face and content validity of the instrument and then tested the instrument based on two simulated scenarios. Completed forms were graded to test the inter-rater reliability of the instrument. Face and content validity were confirmed with participants expressing that the instrument would assist in better reporting of attacks on health in the setting of eastern Burma where they work. Participants were able to give an accurate account of relevant incidents (86% and 82% on Scenarios 1 and 2 respectively). Item-by-item review of the instrument revealed that greater than 95% of participants completed the correct sections. Errors primarily occurred in quantifying the impact of the incident on patient care. Revisions to the translated instrument based on the results consisted primarily of design improvements and simplification of some numerical fields. This instrument was validated for use in eastern Burma and could be used as a model for reporting violence towards health care in other conflict settings.


Bleeding after childbirth / miscarriage - practical notes on the examination of biopsy material.
Postpartum haemorrhage is a significant cause of maternal morbidity and mortality worldwide. The pathologist encounters only a limited spectrum of causes leading to postpartum haemorrhage. The most common causes are retained placenta and placental site subinvolution. Both of these lesions can be diagnosed from material obtained by uterine curettage. Morbidly adherent placenta (placenta accreta spectrum) is a less frequent subject of investigation, the diagnosis of which can be reliably established only on the basis of histological examination of uterine specimens after hysterectomy.


Problems encountered in the immunoassay of alpha-foetoprotein in patients with hepatoma.
Immunoradiometric assays suffer from the phenomenon of paradoxical increase in count rate with increasing dilution of highly concentrated samples--the "hook-effect". This is particularly important for alpha-foetoprotein where in hepatoma may be thousands of times the upper limit of the range of immunoradiometric assays. Using a commercial kit method we have encountered some degree of hook effect in many patients with hepatoma. Significant hooking occurred after 1,000 to 2,000 micrograms/1 but the extent of the effect was sample dependent. Of the samples tested so far, only one patient produced a hook which extended into the standard curve counts range. This resulted in a measured values of 20 micrograms/1 (value on dilution: 100,000 micrograms/1). We recommend that this method should be used routinely in conjunction with a screening method e.g., counterimmunoelectrophoresis and that quantitation of very high values should be by radial immunodiffusion or a method with similar sensitivity.


Responding to the challenge of leprosy-related disability and ultra-poverty.
The Millennium Development Goals have provided much needed attention to extreme poverty reduction. However, people with disabilities are disproportionately affected by poverty and in some countries, even the goal of US$1 per day is far out of reach. For people with leprosy-related disability living in ultra-poverty (on less than 50 cents a day), many mainstream poverty reduction strategies are inaccessible and inappropriate. A project in north-west Bangladesh developed a more contextually meaningful definition of ultra-poverty according to nutrition energy intake. A total of 2372 people with leprosy-related disability were surveyed. Of those, 1285 individuals fell below the ultra-poverty line. Individualised interventions were implemented over an extended period of time, comprised of targeted practical assistance, enhancing community links, advocacy for entitlements, and further linking with other initiatives. Follow-up data available for 856 individuals showed an average increase in per capita income of 83%. Personal contribution to the family income increased by 65%. There was a 51% increase in families having access to a latrine. Finally families reported eating 30% more meals per day, up from an average of two meals per day. The initiative sought to address poverty in a wide variety of ways, using minimal inputs. Over several years, the results indicate a significant change in the economic situation of individuals with leprosy related disabilities. Other organisations are encouraged to duplicate the intervention and share their results.


[Electron microscopic study of intestinal auto-, allo- and xenotransplants in the 1st hours following extracorporeal perfusion].
Mucous membrane ultrastructure was studied after extracorporeal perfusion of the small intestine under auto- (12 experiments), allo- (10 experiments) and xenotransplantations (4 experiments). In all mucosal structures the lesions are demonstrated to depend on nonspecific factors on the one hand, and on genetically foreigh tissue, on the other hand. In every experimental group, the earliest changes occur in microcirculatory bed. Disorders in vessel and blood flow tone lymphotasis and interstitial edema result in disturbances of capillary-epithelial interrelations and metabolic processes. Destructive changes are followed by tissue neutrophilosis, activation of macrophages and plasmocytic cells, degranulation of eosinophil, enterochromaffin and mast cells, profound mucin excretion. Unlike autoperfusion, alloperfusion is characterized by massive neutrophillic degranulation and more severe lesions of mucosal structures. At allotransplantation, neutrophil cell reaction (nonspecific by its nature) is supposed to be the earliest and primary in the course of establishing transplantation immunity. At xenotransplantation, intestinal destruction, developing and rapidly progressing, is connected with the influence of natural antibodies.